Cellular iron uptake, trafficking and metabolism: Key molecules and mechanisms and their roles in disease

• Iron is a crucial transition metal for virtually all life.
• Imported iron is stored or utilized with the cytoplasm or mitochondria.
• Iron storage in ferritin involves iron chaperones (e.g., PCBPs).
• Utilized iron is employed in anabolic pathways in cytoplasm/mitochondria.
• Defects in iron trafficking lead to various human diseases.

Iron is a crucial transition metal for virtually all life. Two major destinations of iron within mammalian cells are the cytosolic iron-storage protein, ferritin, and mitochondria. In mitochondria, iron is utilized in critical anabolic pathways, including: iron-storage in mitochondrial ferritin, heme synthesis, and iron–sulfur cluster (ISC) biogenesis. Although the pathways involved in ISC synthesis in the mitochondria and cytosol have begun to be characterized, many crucial details remain unknown. In this review, we discuss major aspects of the journey of iron from its initial cellular uptake, its modes of trafficking within cells, to an overview of its downstream utilization in the cytoplasm and within mitochondria. The understanding of mitochondrial iron processing and its communication with other organelles/subcellular locations, such as the cytosol, has been elucidated by the analysis of certain diseases e.g., Friedreich's ataxia. Increased knowledge of the molecules and their mechanisms of action in iron processing pathways (e.g., ISC biogenesis) will shape the investigation of iron metabolism in human health and disease.

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